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Title: Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
Author: Dámaso, Estela
González Acosta, María Isabel
Vargas Parra, Gardenía María
Navarro, Matilde
Balmaña, Judith
Ramon y Cajal, Teresa
Tuset, Noemí
Thompson, Bryony A.
Marín, Fátima
Fernández, Anna
Gomez, Carolina
Velasco, Àngela
Solanes, Ares
Iglesias Casals, Sílvia
Urgel, Gisela
López, Consol
Valle, Jesús del
Campos, Olga
Santacana, Maria
Matias-Guiu, Xavier
Lázaro García, Conxi
Valle, Laura
Brunet, Joan
Pineda Riu, Marta
Capellá, G. (Gabriel)
Keywords: Càncer colorectal
Colorectal cancer
Issue Date: 1-Jul-2020
Publisher: MDPI
Abstract: The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutionalMLH1epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS.
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It is part of: Cancers, 2020, vol. 12, num. 7
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Appears in Collections:Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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